LONG-TERM OUTCOME OF ALTERNATING NILOTINIB 400 MG TWICE DAILY AND IMATINIB 400 MG ONCE DAILY AS FIRST-LINE TREATMENT OF CHRONIC MYELOID LEUKEMIA: A PHASE 2 STUDY OF THE GIMEMA CML WORKING PARTY
(Abstract release date: 05/21/15)
EHA Library. Gugliotta G. 06/13/15; 103206; S488
Disclosure(s): S.Orsola-Malpighi HospitalDepartment of Experimental, Diagnostic and Specialty Medicine, University of Bologna, S.Orsola-Malpighi Hospital
Dr. Gabriele Gugliotta
Contributions
Contributions
Abstract
Abstract: S488
Type: Oral Presentation + travel grant
Presentation during EHA20: From 13.06.2015 16:15 to 13.06.2015 16:30
Location: Room A8
Background
Imatinib (IM) is the standard treatment for Ph+ Chronic Myeloid Leukemia (CML) in early Chronic Phase (ECP). Nilotinib (NIL) has demonstrated superior efficacy to IM (phase 3 ENESTnd trial). The treatment with more than one TKI, according to the principles of cancer poly-chemotherapy, may improve the response rates and may decrease the frequency of drug-resistance. The combination of different TKIs is potentially toxic, difficult to be explored in the ECP setting, while the alternating administration of IM and NIL could be better tolerated.
Aims
To evaluate the response (either cytogenetic and molecular) and the long-term outcome of ECP Ph+ CML pts treated with the alternating administration of NIL and IM.
Methods
Phase 2 study (ClinicalTrials.gov. NCT00769327). Schedule: NIL 400 mg twice daily for the first 3 months; IM 400 mg daily for the next 3 months; then, NIL and IM rotating every 3 months, for a total duration of 24 months (study core). The primary end-point was the Complete Cytogenetic Response (CCyR) rate at 12 months. The pts remained on study unless both drugs were discontinued. Definition of failure: according to 2013 ELN recommendations; event: failure, permanent discontinuation of both drug for any reason, patient refusal of alternating schedule during the study core. All the analysis was performed according to the ITT principle.
Results
123 pts were enrolled in 38 Italian hematologic Centers; median age 56 years (range 18-84); 33% low, 45% intermediate and 22% high Sokal score; 94% low EUTOS score; median follow-up 60 months. The CCyR rates at early milestones were: 68% at 3 months, 73% at 6 months and 67% at 12 months (primary efficacy variable). The cumulative CCyR rate by 60 months was 93%. The cumulative MMR rates by 12 and 60 months were 82% and 84%, respectively. The cumulative MR4.0 rates by 12, 24 and 60 months were 43%, 61% and 62%, respectively. At the end of the 60 months, 69% of pts were on study, being the majority on monotherapy with NIL (35%) or IM (23%), and only 11% still on alternating schedule. Events were observed in 52 (42%) pts: 22 failures, 13 adverse events; 14 patient refusal; 3 others. Failures included: 7 (5.6%) progressions to accelerated/blast phase (AP/BP); 5 primary resistances; 9 secondary resistances. The progressions to AP/BP occurred after a median time of 10 months (4-25 months); 4 pts had an ABL mutation (2 T315I, 1 Y253H, 1 F359V); all pts subsequently died. Athero-thrombotic adverse events (AAE) were observed in 6 (4.8%) pts: 3 acute myocardial infarctions, 1 unstable angina, 1 peripheral arterial occlusive disease and 1 aortic atherosclerosis. All pts discontinued permanently NIL and were treated with IM (4 pts) or dasatinib (2 pts). Overall, 12 pts died: 7 for progression to AP/BP, 2 for a second malignancy, 1 after ASCT, 1 for pulmonary embolism, and 1 for cerebral hemorrhage. The 5-year overall survival, progression-free survival, failure-free survival and event-free survival were 90%, 90%, 78% and 57%, respectively.
Summary
The early response rates achieved with the alternating administration of NIL and IM seem to be higher compared to historical data with IM alone; however, no difference seems evident in the long-term. Moreover, we observed a high number of progressions to AP/BP, which can be only partially justified by the relevant proportion of pts at intermediate or high Sokal risk. If compared to the results of NIL as monotherapy in ECP CML, this final analysis, despite the lower rate of AAE, does not support the alternating schedule of NIL and IM as first-line treatment of ECP CML.
Keyword(s): Chronic myeloid leukemia, Long-term follow-up, Tyrosine kinase inhibitor
Session topic: CML: Clinical trials
Type: Oral Presentation + travel grant
Presentation during EHA20: From 13.06.2015 16:15 to 13.06.2015 16:30
Location: Room A8
Background
Imatinib (IM) is the standard treatment for Ph+ Chronic Myeloid Leukemia (CML) in early Chronic Phase (ECP). Nilotinib (NIL) has demonstrated superior efficacy to IM (phase 3 ENESTnd trial). The treatment with more than one TKI, according to the principles of cancer poly-chemotherapy, may improve the response rates and may decrease the frequency of drug-resistance. The combination of different TKIs is potentially toxic, difficult to be explored in the ECP setting, while the alternating administration of IM and NIL could be better tolerated.
Aims
To evaluate the response (either cytogenetic and molecular) and the long-term outcome of ECP Ph+ CML pts treated with the alternating administration of NIL and IM.
Methods
Phase 2 study (ClinicalTrials.gov. NCT00769327). Schedule: NIL 400 mg twice daily for the first 3 months; IM 400 mg daily for the next 3 months; then, NIL and IM rotating every 3 months, for a total duration of 24 months (study core). The primary end-point was the Complete Cytogenetic Response (CCyR) rate at 12 months. The pts remained on study unless both drugs were discontinued. Definition of failure: according to 2013 ELN recommendations; event: failure, permanent discontinuation of both drug for any reason, patient refusal of alternating schedule during the study core. All the analysis was performed according to the ITT principle.
Results
123 pts were enrolled in 38 Italian hematologic Centers; median age 56 years (range 18-84); 33% low, 45% intermediate and 22% high Sokal score; 94% low EUTOS score; median follow-up 60 months. The CCyR rates at early milestones were: 68% at 3 months, 73% at 6 months and 67% at 12 months (primary efficacy variable). The cumulative CCyR rate by 60 months was 93%. The cumulative MMR rates by 12 and 60 months were 82% and 84%, respectively. The cumulative MR4.0 rates by 12, 24 and 60 months were 43%, 61% and 62%, respectively. At the end of the 60 months, 69% of pts were on study, being the majority on monotherapy with NIL (35%) or IM (23%), and only 11% still on alternating schedule. Events were observed in 52 (42%) pts: 22 failures, 13 adverse events; 14 patient refusal; 3 others. Failures included: 7 (5.6%) progressions to accelerated/blast phase (AP/BP); 5 primary resistances; 9 secondary resistances. The progressions to AP/BP occurred after a median time of 10 months (4-25 months); 4 pts had an ABL mutation (2 T315I, 1 Y253H, 1 F359V); all pts subsequently died. Athero-thrombotic adverse events (AAE) were observed in 6 (4.8%) pts: 3 acute myocardial infarctions, 1 unstable angina, 1 peripheral arterial occlusive disease and 1 aortic atherosclerosis. All pts discontinued permanently NIL and were treated with IM (4 pts) or dasatinib (2 pts). Overall, 12 pts died: 7 for progression to AP/BP, 2 for a second malignancy, 1 after ASCT, 1 for pulmonary embolism, and 1 for cerebral hemorrhage. The 5-year overall survival, progression-free survival, failure-free survival and event-free survival were 90%, 90%, 78% and 57%, respectively.
Summary
The early response rates achieved with the alternating administration of NIL and IM seem to be higher compared to historical data with IM alone; however, no difference seems evident in the long-term. Moreover, we observed a high number of progressions to AP/BP, which can be only partially justified by the relevant proportion of pts at intermediate or high Sokal risk. If compared to the results of NIL as monotherapy in ECP CML, this final analysis, despite the lower rate of AAE, does not support the alternating schedule of NIL and IM as first-line treatment of ECP CML.
Acknowledgements: European LeukemiaNet, BolognAIL
Keyword(s): Chronic myeloid leukemia, Long-term follow-up, Tyrosine kinase inhibitor
Session topic: CML: Clinical trials
Abstract: S488
Type: Oral Presentation + travel grant
Presentation during EHA20: From 13.06.2015 16:15 to 13.06.2015 16:30
Location: Room A8
Background
Imatinib (IM) is the standard treatment for Ph+ Chronic Myeloid Leukemia (CML) in early Chronic Phase (ECP). Nilotinib (NIL) has demonstrated superior efficacy to IM (phase 3 ENESTnd trial). The treatment with more than one TKI, according to the principles of cancer poly-chemotherapy, may improve the response rates and may decrease the frequency of drug-resistance. The combination of different TKIs is potentially toxic, difficult to be explored in the ECP setting, while the alternating administration of IM and NIL could be better tolerated.
Aims
To evaluate the response (either cytogenetic and molecular) and the long-term outcome of ECP Ph+ CML pts treated with the alternating administration of NIL and IM.
Methods
Phase 2 study (ClinicalTrials.gov. NCT00769327). Schedule: NIL 400 mg twice daily for the first 3 months; IM 400 mg daily for the next 3 months; then, NIL and IM rotating every 3 months, for a total duration of 24 months (study core). The primary end-point was the Complete Cytogenetic Response (CCyR) rate at 12 months. The pts remained on study unless both drugs were discontinued. Definition of failure: according to 2013 ELN recommendations; event: failure, permanent discontinuation of both drug for any reason, patient refusal of alternating schedule during the study core. All the analysis was performed according to the ITT principle.
Results
123 pts were enrolled in 38 Italian hematologic Centers; median age 56 years (range 18-84); 33% low, 45% intermediate and 22% high Sokal score; 94% low EUTOS score; median follow-up 60 months. The CCyR rates at early milestones were: 68% at 3 months, 73% at 6 months and 67% at 12 months (primary efficacy variable). The cumulative CCyR rate by 60 months was 93%. The cumulative MMR rates by 12 and 60 months were 82% and 84%, respectively. The cumulative MR4.0 rates by 12, 24 and 60 months were 43%, 61% and 62%, respectively. At the end of the 60 months, 69% of pts were on study, being the majority on monotherapy with NIL (35%) or IM (23%), and only 11% still on alternating schedule. Events were observed in 52 (42%) pts: 22 failures, 13 adverse events; 14 patient refusal; 3 others. Failures included: 7 (5.6%) progressions to accelerated/blast phase (AP/BP); 5 primary resistances; 9 secondary resistances. The progressions to AP/BP occurred after a median time of 10 months (4-25 months); 4 pts had an ABL mutation (2 T315I, 1 Y253H, 1 F359V); all pts subsequently died. Athero-thrombotic adverse events (AAE) were observed in 6 (4.8%) pts: 3 acute myocardial infarctions, 1 unstable angina, 1 peripheral arterial occlusive disease and 1 aortic atherosclerosis. All pts discontinued permanently NIL and were treated with IM (4 pts) or dasatinib (2 pts). Overall, 12 pts died: 7 for progression to AP/BP, 2 for a second malignancy, 1 after ASCT, 1 for pulmonary embolism, and 1 for cerebral hemorrhage. The 5-year overall survival, progression-free survival, failure-free survival and event-free survival were 90%, 90%, 78% and 57%, respectively.
Summary
The early response rates achieved with the alternating administration of NIL and IM seem to be higher compared to historical data with IM alone; however, no difference seems evident in the long-term. Moreover, we observed a high number of progressions to AP/BP, which can be only partially justified by the relevant proportion of pts at intermediate or high Sokal risk. If compared to the results of NIL as monotherapy in ECP CML, this final analysis, despite the lower rate of AAE, does not support the alternating schedule of NIL and IM as first-line treatment of ECP CML.
Keyword(s): Chronic myeloid leukemia, Long-term follow-up, Tyrosine kinase inhibitor
Session topic: CML: Clinical trials
Type: Oral Presentation + travel grant
Presentation during EHA20: From 13.06.2015 16:15 to 13.06.2015 16:30
Location: Room A8
Background
Imatinib (IM) is the standard treatment for Ph+ Chronic Myeloid Leukemia (CML) in early Chronic Phase (ECP). Nilotinib (NIL) has demonstrated superior efficacy to IM (phase 3 ENESTnd trial). The treatment with more than one TKI, according to the principles of cancer poly-chemotherapy, may improve the response rates and may decrease the frequency of drug-resistance. The combination of different TKIs is potentially toxic, difficult to be explored in the ECP setting, while the alternating administration of IM and NIL could be better tolerated.
Aims
To evaluate the response (either cytogenetic and molecular) and the long-term outcome of ECP Ph+ CML pts treated with the alternating administration of NIL and IM.
Methods
Phase 2 study (ClinicalTrials.gov. NCT00769327). Schedule: NIL 400 mg twice daily for the first 3 months; IM 400 mg daily for the next 3 months; then, NIL and IM rotating every 3 months, for a total duration of 24 months (study core). The primary end-point was the Complete Cytogenetic Response (CCyR) rate at 12 months. The pts remained on study unless both drugs were discontinued. Definition of failure: according to 2013 ELN recommendations; event: failure, permanent discontinuation of both drug for any reason, patient refusal of alternating schedule during the study core. All the analysis was performed according to the ITT principle.
Results
123 pts were enrolled in 38 Italian hematologic Centers; median age 56 years (range 18-84); 33% low, 45% intermediate and 22% high Sokal score; 94% low EUTOS score; median follow-up 60 months. The CCyR rates at early milestones were: 68% at 3 months, 73% at 6 months and 67% at 12 months (primary efficacy variable). The cumulative CCyR rate by 60 months was 93%. The cumulative MMR rates by 12 and 60 months were 82% and 84%, respectively. The cumulative MR4.0 rates by 12, 24 and 60 months were 43%, 61% and 62%, respectively. At the end of the 60 months, 69% of pts were on study, being the majority on monotherapy with NIL (35%) or IM (23%), and only 11% still on alternating schedule. Events were observed in 52 (42%) pts: 22 failures, 13 adverse events; 14 patient refusal; 3 others. Failures included: 7 (5.6%) progressions to accelerated/blast phase (AP/BP); 5 primary resistances; 9 secondary resistances. The progressions to AP/BP occurred after a median time of 10 months (4-25 months); 4 pts had an ABL mutation (2 T315I, 1 Y253H, 1 F359V); all pts subsequently died. Athero-thrombotic adverse events (AAE) were observed in 6 (4.8%) pts: 3 acute myocardial infarctions, 1 unstable angina, 1 peripheral arterial occlusive disease and 1 aortic atherosclerosis. All pts discontinued permanently NIL and were treated with IM (4 pts) or dasatinib (2 pts). Overall, 12 pts died: 7 for progression to AP/BP, 2 for a second malignancy, 1 after ASCT, 1 for pulmonary embolism, and 1 for cerebral hemorrhage. The 5-year overall survival, progression-free survival, failure-free survival and event-free survival were 90%, 90%, 78% and 57%, respectively.
Summary
The early response rates achieved with the alternating administration of NIL and IM seem to be higher compared to historical data with IM alone; however, no difference seems evident in the long-term. Moreover, we observed a high number of progressions to AP/BP, which can be only partially justified by the relevant proportion of pts at intermediate or high Sokal risk. If compared to the results of NIL as monotherapy in ECP CML, this final analysis, despite the lower rate of AAE, does not support the alternating schedule of NIL and IM as first-line treatment of ECP CML.
Acknowledgements: European LeukemiaNet, BolognAIL
Keyword(s): Chronic myeloid leukemia, Long-term follow-up, Tyrosine kinase inhibitor
Session topic: CML: Clinical trials
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